Understanding of the cell biology of cancer may allow us to unravel the carcinogenic process to a point where we can rationally and effectively intervene. This may also facilitate the rational design and development of novel cancer chemo- therapeutic agents. We have undertaken a multidirectional approach to carcinogenesis and chemotherapy which involved studies on the cell biology of normal and malignant tissues from both humans and rodents. Methodologies were established to develop and characterize numerous cell lines from normal human kidney tissues. These cell lines include both cortical epithelial cell cultures as well as defined proximal tubular cell populations. The availability of well defined normal human kidney cell lines will allow for detailed pharmacologic and toxicologic studies under defined in vitro conditions. Studies directed towards understanding the cell biology of lung cancer have had to rely on the use of human lung cancer cell lines since normal proliferating cultures of peripheral lung epithelium were not available for comparative studies. We have developed new culture methodologies which allowed for the establishment of differentiated alveolar type II cells from rat lung. These developments will allow for detailed studies on the effects of toxins, carcinogens and anticancer drugs on normal lung cells under in vitro conditions where proliferation and differentation can be controlled. Liver cancer cell biology studies which involved chemical transformation of normal rat liver epithelial cells demonstrated that there was a clonal relationship between the two most prominent types of liver cancer, namely hepatocellular carcinomas and cholangiocarcinomas. These findings have now been further substantiated utilizing cell-type specific monoclonal antibodies. These studies may lead to the elucidation of the cell types responsible for liver cancer and to more effective therapy.